tbuckley/cabot-search huggingface dataset:
17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes
Authors: Kathryn R. Bowles, Derian A. Pugh, Yiyuan Liu, Tulsi Patel, Alan E. Renton, Sara Bandres-Ciga, Ziv Gan-Or, Peter Heutink, Ari Siitonen, Sarah Bertelsen, Jonathan D. Cherry, Celeste M. Karch, Steven J. Frucht, Brian H. Kopell, Inga Peter, Y. J. Park, Alexander Charney, Towfique Raj, John F. Crary, A. M. Goate
Journal: Molecular Neurodegeneration (2022)

Parkinson's disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified.To better understand the genetic contribution of this region to PD and to identify novel mechanisms conferring risk for the disease, we fine-mapped the 17q21.31 locus by constructing discrete haplotype blocks from genetic data. We used digital PCR to assess copy number variation associated with PD-associated blocks, and used human brain postmortem RNA-seq data to identify candidate genes that were then further investigated using in vitro models and human brain tissue.We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble α-synuclein, and co-localized with Lewy bodies in PD brain tissue.These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with α-synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.
Sodium–Glucose Cotransporter 2 Inhibitors in Cardiovascular and Renal Outcomes in Patients With Diabetes but Without Established Cardiovascular Disease: A Nationwide Population-Based Cohort Study
Authors: Hao-Chih Chang, Tzu-Ting Kuo, Yun-Yu Chen, Yenn-Jiang Lin, Hung-Yu Chang, Chung-Lieh Hung, Fa-Po Chung
Journal: Diabetes Care (2022)
Patient‐centered dupilumab dosing regimen leads to successful dose reduction in persistently controlled atopic dermatitis
Authors: Lotte S. Spekhorst, Daphne Bakker, Julia Drylewicz, Theo Rispens, Floris Loeff, Celeste M. Boesjes, Judith Thijs, Geertruida L. E. Romeijn, Laura Loman, Marie‐Louise Schuttelaar, Femke van Wijk, Marlies de Graaf, Marjolein S. de Bruin‐Weller
Journal: Allergy (2022)

Abstract Background At present, no real‐world studies are available on different dupilumab dosing regimens in controlled atopic dermatitis (AD). The aim of this study was to clinically evaluate a patient‐centered dupilumab dosing regimen in patients with controlled AD and to relate this to serum drug levels and serum biomarkers. Methods Ninety adult AD patients from the prospective BioDay registry were included based on their dupilumab administration interval according to a predefined patient‐centered dosing regimen. Group A ( n = 30) did not fulfill the criteria for interval prolongation and continued using the standard dupilumab dosage (300 mg/2 weeks), group B ( n = 30) prolonged dupilumab interval with 50% (300 mg/4 weeks), and group C ( n = 30) prolonged dupilumab interval with 66%–75% (300 mg/6–8 weeks). AD severity score, patient‐reported outcomes, serum dupilumab levels, and serum biomarkers were analyzed over time. Results Disease severity scores did not significantly change over time during the tapering period in any of the groups. In groups B and C, the Numeric Rating Scale (NRS)‐pruritus temporarily significantly increased after interval prolongation but remained low (median NRS‐pruritus≤4). Median dupilumab levels remained stable in group A (standard dosage), but significantly decreased in groups B and C (24.1 mg/L (IQR = 17.1–45.6); 12.5 mg/L (IQR = 1.7–22.3)) compared with the levels during the standard dosage (88.2 mg/L [IQR = 67.1–123.0, p &lt; .001]). Disease severity biomarker levels (CCL17/CCL18) remained low in all study groups during the whole observation period. Conclusions This study showed that dose reduction was successful in a subgroup of patients with controlled AD by using a patient‐centered dosing regimen. These patients showed stable low disease activity and low severity biomarkers over time.
Snail acetylation by autophagy‐derived acetyl‐coenzyme A promotes invasion and metastasis of <i>KRAS</i>‐<i>LKB1</i> co‐mutated lung cancer cells
Authors: Jang Hee Han, Yong Keon Kim, Hakhyun Kim, Jooyoung Lee, Myung Joon Oh, Sang Bum Kim, Minjee Kim, Kook Hwan Kim, Hyun Ju Yoon, Myung‐Shik Lee, John D. Minna, Michael A. White, Hyun Seok Kim
Journal: Cancer Communications (2022)

Abstract Background Autophagy is elevated in metastatic tumors and is often associated with active epithelial‐to‐mesenchymal transition (EMT). However, the extent to which EMT is dependent on autophagy is largely unknown. This study aimed to identify the mechanisms by which autophagy facilitates EMT. Methods We employed a liquid chromatography‐based metabolomic approach with kirsten rat sarcoma viral oncogene ( KRAS ) and liver kinase B1 ( LKB1 ) gene co‐mutated (KL) cells that represent an autophagy/EMT‐coactivated invasive lung cancer subtype for the identification of metabolites linked to autophagy‐driven EMT activation. Molecular mechanisms of autophagy‐driven EMT activation were further investigated by quantitative real‐time polymerase chain reaction (qRT‐PCR), Western blotting analysis, immunoprecipitation, immunofluorescence staining, and metabolite assays. The effects of chemical and genetic perturbations on autophagic flux were assessed by two orthogonal approaches: microtubule‐associated protein 1A/1B‐light chain 3 (LC3) turnover analysis by Western blotting and monomeric red fluorescent protein‐green fluorescent protein (mRFP‐GFP)‐LC3 tandem fluorescent protein quenching assay. Transcription factor EB (TFEB) activity was measured by coordinated lysosomal expression and regulation (CLEAR) motif‐driven luciferase reporter assay. Experimental metastasis (tail vein injection) mouse models were used to evaluate the impact of calcium/calmodulin‐dependent protein kinase kinase 2 (CAMKK2) or ATP citrate lyase (ACLY) inhibitors on lung metastasis using IVIS luciferase imaging system. Results We found that autophagy in KL cancer cells increased acetyl‐coenzyme A (acetyl‐CoA), which facilitated the acetylation and stabilization of the EMT‐inducing transcription factor Snail. The autophagy/acetyl‐CoA/acetyl‐Snail axis was further validated in tumor tissues and in autophagy‐activated pancreatic cancer cells. TFEB acetylation in KL cancer cells sustained pro‐metastatic autophagy in a mammalian target of rapamycin complex 1 (mTORC1)‐independent manner. Pharmacological inhibition of this axis via CAMKK2 inhibitors or ACLY inhibitors consistently reduced the metastatic capacity of KL cancer cells in vivo. Conclusions This study demonstrates that autophagy‐derived acetyl‐CoA promotes Snail acetylation and thereby facilitates invasion and metastasis of KRAS‐LKB1 co‐mutated lung cancer cells and that inhibition of the autophagy/acetyl‐CoA/acetyl‐Snail axis using CAMKK2 or ACLY inhibitors could be a potential therapeutic strategy to suppress metastasis of KL lung cancer.
Calcineurin Controls Hypothalamic NMDA Receptor Activity and Sympathetic Outflow
Authors: Jing-Jing Zhou, Jian-Ying Shao, Shao-Rui Chen, Hui-Lin Pan
Journal: Circulation Research (2022)

Rationale: Hypertension is a common and serious adverse effect of calcineurin inhibitors, including cyclosporine and tacrolimus (FK506). Although increased sympathetic nerve discharges are associated with calcineurin inhibitor–induced hypertension, the sources of excess sympathetic outflow and underlying mechanisms remain elusive. Calcineurin (protein phosphatase-2B) is broadly expressed in the brain, including the paraventricular nuclear (PVN) of the hypothalamus, which is critically involved in regulating sympathetic vasomotor tone. Objective: We determined whether prolonged treatment with the calcineurin inhibitor causes elevated sympathetic output and persistent hypertension by potentiating synaptic N-methyl-D-aspartate (NMDA) receptor activity in the PVN. Methods and Results: Telemetry recordings showed that systemic administration of FK506 (3 mg/kg per day) for 14 days caused a gradual and profound increase in arterial blood pressure in rats, which lasted at least 7 days after discontinuing FK506 treatment. Correspondingly, systemic treatment with FK506 markedly reduced calcineurin activity in the PVN and circumventricular organs, but not rostral ventrolateral medulla, and increased the phosphorylation level and synaptic trafficking of NMDA receptors in the PVN. Immunocytochemistry labeling showed that calcineurin was expressed in presympathetic neurons in the PVN. Whole-cell patch-clamp recordings in brain slices revealed that treatment with FK506 increased baseline firing activity of PVN presympathetic neurons; this increase was blocked by the NMDA or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist. Also, treatment with FK506 markedly increased presynaptic and postsynaptic NMDA receptor activity of PVN presympathetic neurons. Furthermore, microinjection of the NMDA or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist into the PVN of anesthetized rats preferentially attenuated renal sympathetic nerve discharges and blood pressure elevated by FK506 treatment. In addition, systemic administration of memantine, a clinically used NMDA receptor antagonist, effectively attenuated FK506 treatment–induced hypertension in conscious rats. Conclusions: Our findings reveal that normal calcineurin activity in the PVN constitutively restricts sympathetic vasomotor tone via suppressing NMDA receptor activity, which may be targeted for treating calcineurin inhibitor–induced hypertension.
Association of Postsurgical Opioid Refills for Patients With Risk of Opioid Misuse and Chronic Opioid Use Among Family Members
Authors: Denis Agniel, Gabriel A. Brat, Jayson S. Marwaha, Kathe Fox, Daniel Knecht, Harold L. Paz, Mark C. Bicket, Brian Yorkgitis, Nathan Palmer, Isaac Kohane
Journal: JAMA Network Open (2022)

The US health care system is experiencing a sharp increase in opioid-related adverse events and spending, and opioid overprescription may be a key factor in this crisis. Ambient opioid exposure within households is one of the known major dangers of overprescription.
β2-Microglobulin Maintains Glioblastoma Stem Cells and Induces M2-like Polarization of Tumor-Associated Macrophages
Authors: Daqi Li, Qian Zhang, Lu Li, Kexin Chen, Junlei Yang, Deobrat Dixit, Ryan C. Gimple, Shusheng Ci, Chenfei Lu, Lang Hu, Jiancheng Gao, Danyang Shan, Yangqing Li, Junxia Zhang, Zhumei Shi, Danling Gu, Wei Yuan, Qiulian Wu, Kailin Yang, Linjie Zhao, Zhixin Qiu, Deguan Lv, Wei Gao, Hui Yang, Fan Lin, Qianghu Wang, Jianghong Man, Chaojun Li, Weiwei Tao, Sameer Agnihotri, Xu Qian, Yu Shi, Yongping You, Nu Zhang, Jeremy N. Rich, Xiuxing Wang
Journal: Cancer Research (2022)

Abstract Glioblastoma (GBM) is a complex ecosystem that includes a heterogeneous tumor population and the tumor-immune microenvironment (TIME), prominently containing tumor-associated macrophages (TAM) and microglia. Here, we demonstrated that β2-microglobulin (B2M), a subunit of the class I major histocompatibility complex (MHC-I), promotes the maintenance of stem-like neoplastic populations and reprograms the TIME to an anti-inflammatory, tumor-promoting state. B2M activated PI3K/AKT/mTOR signaling by interacting with PIP5K1A in GBM stem cells (GSC) and promoting MYC-induced secretion of transforming growth factor-β1 (TGFβ1). Inhibition of B2M attenuated GSC survival, self-renewal, and tumor growth. B2M-induced TGFβ1 secretion activated paracrine SMAD and PI3K/AKT signaling in TAMs and promoted an M2-like macrophage phenotype. These findings reveal tumor-promoting functions of B2M and suggest that targeting B2M or its downstream axis may provide an effective approach for treating GBM. Significance: β2-microglobulin signaling in glioblastoma cells activates a PI3K/AKT/MYC/TGFβ1 axis that maintains stem cells and induces M2-like macrophage polarization, highlighting potential therapeutic strategies for targeting tumor cells and the immunosuppressive microenvironment in glioblastoma.
Correction: The outcome of patients with Hodgkin lymphoma and early relapse after autologous stem cell transplant has improved in recent years
Authors: Ali Bazarbachi, Ariane Boumendil, Hervé Finel, Irma Khvedelidze, Joanna Romejko-Jarosinska, Alina Tanase, Saad Akhtar, Tarek Ben Othman, Mohammad Ma’koseh, Boris Afanasyev, Jean El-Cheikh, Javier Briones, Zafer Gülbas, Rose-Marie Hamladji, Tugrul Elverdi, Didier Blaise, Carmen Martínez, Eleonora Alma, Kazimierz Halaburda, Aida Botelho Sousa, Bertram Glass, Steven Robinson, Silvia Montoto, Anna Sureda
Journal: Leukemia (2022)
Effectiveness of 2, 3, and 4 COVID-19 mRNA Vaccine Doses Among Immunocompetent Adults During Periods when SARS-CoV-2 Omicron BA.1 and BA.2/BA.2.12.1 Sublineages Predominated — VISION Network, 10 States, December 2021–June 2022
Authors: Ruth Link-Gelles, Matthew E. Levy, Manjusha Gaglani, Stephanie A. Irving, Melissa Stockwell, Kristin Dascomb, Malini B. DeSilva, Sarah E. Reese, I-Chia Liao, Toan C. Ong, Shaun J. Grannis, Charlene McEvoy, Palak Patel, Nicola P. Klein, Emily Hartmann, Edward Stenehjem, Karthik Natarajan, Allison L. Naleway, Kempapura Murthy, Suchitra Rao, Brian E. Dixon, Anupam B. Kharbanda, Akintunde Akinseye, Monica Dickerson, Ned Lewis, Nancy Grisel, Jungmi Han, Michelle A. Barron, William F. Fadel, Margaret M. Dunne, Kristin Goddard, Julie Arndorfer, Deepika Konatham, Nimish R. Valvi, J. C. Currey, Bruce Fireman, Chandni Raiyani, Ousseny Zerbo, Chantel Sloan-Aagard, Sarah W. Ball, Mark G. Thompson, Mark W. Tenforde
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

The Omicron variant (B.1.1.529) of SARS-CoV-2, the virus that causes COVID-19, was first identified in the United States in November 2021, with the BA.1 sublineage (including BA.1.1) causing the largest surge in COVID-19 cases to date. Omicron sublineages BA.2 and BA.2.12.1 emerged later and by late April 2022, accounted for most cases.* Estimates of COVID-19 vaccine effectiveness (VE) can be reduced by newly emerging variants or sublineages that evade vaccine-induced immunity (1), protection from previous SARS-CoV-2 infection in unvaccinated persons (2), or increasing time since vaccination (3). Real-world data comparing VE during the periods when the BA.1 and BA.2/BA.2.12.1 predominated (BA.1 period and BA.2/BA.2.12.1 period, respectively) are limited. The VISION network† examined 214,487 emergency department/urgent care (ED/UC) visits and 58,782 hospitalizations with a COVID-19-like illness§ diagnosis among 10 states during December 18, 2021-June 10, 2022, to evaluate VE of 2, 3, and 4 doses of mRNA COVID-19 vaccines (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) compared with no vaccination among adults without immunocompromising conditions. VE against COVID-19-associated hospitalization 7-119 days and ≥120 days after receipt of dose 3 was 92% (95% CI = 91%-93%) and 85% (95% CI = 81%-89%), respectively, during the BA.1 period, compared with 69% (95% CI = 58%-76%) and 52% (95% CI = 44%-59%), respectively, during the BA.2/BA.2.12.1 period. Patterns were similar for ED/UC encounters. Among adults aged ≥50 years, VE against COVID-19-associated hospitalization ≥120 days after receipt of dose 3 was 55% (95% CI = 46%-62%) and ≥7 days (median = 27 days) after a fourth dose was 80% (95% CI = 71%-85%) during BA.2/BA.2.12.1 predominance. Immunocompetent persons should receive recommended COVID-19 booster doses to prevent moderate to severe COVID-19, including a first booster dose for all eligible persons and second booster dose for adults aged ≥50 years at least 4 months after an initial booster dose. Booster doses should be obtained immediately when persons become eligible.¶.
Multiple Coordination‐Derived Bioactive Hydrogel with Proangiogenic Hemostatic Capacity for Wound Repair
Authors: Meng Luo, Yidan Wang, Chenxi Xie, Bo Lei
Journal: Advanced Healthcare Materials (2022)

Abstract Bioactive hydrogels with multifunctional properties have shown promising potential in promoting wound repair and skin tissue regeneration. The regulation on different stages of skin wound healing (hemostasis and inflammation) is important for wound repair. Herein, a multiple coordination‐derived bioactive hydrogel (SGPA) with anti‐inflammatory proangiogenic hemostatic capacity for wound repair is reported. The SGPA is prepared through a facile multiple metal coordination action based on the sodium alginate, metal ions (Gd 3+ ), and bisphosphate functionalized polycitrate. The SGPA exhibits a large porous structure, good injectability, and self‐healing performance, as well as controlled biodegradation. Furthermore, the SGPA has good cytocompatibility and hemocompatibility, and can further promote the migration of endothelial cells. The SGPA hydrogel presents good hemostasis capacity in a liver hemorrhage model in vivo. The full‐thickness cutaneous wound model demonstrates that the SGPA hydrogel can effectively accelerate the wound repair through down‐regulating the inflammatory factors and stimulating the angiogenesis around the wound beds. This work suggests that the multiple metal‐organic coordination may be a good strategy to construct the multifunctional bioactive hydrogel for wound repair.
Changes in Visual Impairment due to Diabetic Retinopathy During 1980–2019 Based on Nationwide Register Data
Authors: Petri K.M. Purola, Matti U.I. Ojamo, Mika Gissler, Hannu M.T. Uusitalo
Journal: Diabetes Care (2022)

OBJECTIVE To evaluate changes in the incidence, prevalence, severity, and onset age of visual impairment (VI) due to diabetic retinopathy (DR) and compare these trends in the screening and treatment of diabetes during 40 years based on Finnish national register data. RESEARCH DESIGN AND METHODS We included people with VI with nonproliferative DR (NPDR; n = 2,490, 73% women) or proliferative DR (PDR; n = 2,026, 53% women) as the main diagnosis for VI during 1980–2019 in the Finnish Register of Visual Impairment. The number of patients with treated diabetes during 1986–2019 was obtained from the Social Insurance Institution of Finland registers based on reimbursed medication data. RESULTS The annual incidence of reported VI due to DR has decreased since it peaked in the 1990s: regarding NPDR, it decreased from 102.3 to 5.5 per 100,000 patients with treated diabetes between the 1990s and 2010s; regarding PDR, the respective change was from 39.9 to 7.4. The incidence of patients with diabetes treated for DR increased during this period. Annual prevalence of reported VI and differences between sexes steadily decreased in the 2000s and 2010s. The severity of reported VI has decreased, and the age at the onset of reported VI increased during the 40 years. CONCLUSIONS Prevalence and incidence of VI due to DR have dramatically decreased and shifted to older age during the 40 years despite the increasing prevalence of diabetes. These positive trends highlight the successful development and effectiveness of screening and therapies for diabetes and DR.
Detecting cell-of-origin and cancer-specific methylation features of cell-free DNA from Nanopore sequencing
Authors: Efrat Katsman, Shari Orlanski, Filippo Martignano, Ilana Fox-Fisher, Ruth Shemer, Yuval Dor, Aviad Zick, Amir Eden, Iacopo Petrini, Silvestro G. Conticello, Benjamin P. Berman
Journal: Genome biology (2022)

The Oxford Nanopore (ONT) platform provides portable and rapid genome sequencing, and its ability to natively profile DNA methylation without complex sample processing is attractive for point-of-care real-time sequencing. We recently demonstrated ONT shallow whole-genome sequencing to detect copy number alterations (CNAs) from the circulating tumor DNA (ctDNA) of cancer patients. Here, we show that cell type and cancer-specific methylation changes can also be detected, as well as cancer-associated fragmentation signatures. This feasibility study suggests that ONT shallow WGS could be a powerful tool for liquid biopsy.
CircBCAR3 accelerates esophageal cancer tumorigenesis and metastasis via sponging miR-27a-3p
Authors: Yong Xi, Yaxing Shen, Donglei Wu, Jingtao Zhang, Chengbin Lin, Lijie Wang, Chaoqun Yu, Bentong Yu, Weiyu Shen
Journal: Molecular Cancer (2022)

Circular RNAs (circRNAs) have been demonstrated to contribute to esophageal cancer progression. CircBCAR3 (hsa_circ_0007624) is predicted to be differentially expressed in esophageal cancer by bioinformatics analysis. We investigated the oncogenic roles and biogenesis of circBCAR3 in esophageal carcinogenesis.Functions of circBCAR3 on cancer cell proliferation, migration, invasion, and ferroptosis were explored using the loss-of-function assays. A xenograft mouse model was used to reveal effects of circBCAR3 on xenograft growth and lung metastasis. The upstream and downstream mechanisms of circBCAR3 were investigated by bioinformatics analysis and confirmed by RNA immunoprecipitation and luciferase reporter assays. The dysregulated genes in hypoxia-induced esophageal cancer cells were identified using RNA-seq.CircBCAR3 was highly expressed in esophageal cancer tissues and cells and its expression was increased by hypoxia in vitro. Silencing of circBCAR3 repressed the proliferation, migration, invasion, and ferroptosis of esophageal cancer cells in vitro, as well as inhibited the growth and metastasis of esophageal xenograft in mice in vivo. The hypoxia-induced promotive effects on esophageal cancer cell migration and ferroptosis were rescued by circBCAR3 knockdown. Mechanistically, circBCAR3 can interact with miR-27a-3p by the competitive endogenous RNA mechanism to upregulate transportin-1 (TNPO1). Furthermore, our investigation indicated that splicing factor quaking (QKI) is a positive regulator of circBCAR3 via targeting the introns flanking the hsa_circ_0007624-formed exons in BCAR3 pre-mRNA. Hypoxia upregulates E2F7 to transcriptionally activate QKI.Our research demonstrated that splicing factor QKI promotes circBCAR3 biogenesis, which accelerates esophageal cancer tumorigenesis via binding with miR-27a-3p to upregulate TNPO1. These data suggested circBCAR3 as a potential target in the treatment of esophageal cancer. Hypoxia induces the upregulation of E2F7, which transcriptionally activates QKI in esophageal cancer cells. QKI increases the formation of circBCAR3 by juxtaposing the circularized exons. CircBCAR3 binds with miR-27a-3p to promote TNPO1 expression. CircBCAR3 promoted the proliferation, migration, invasion, and ferroptosis of esophageal cancer cells by miR-27a-3p.